Inflammation is a key and invariant pathological feature of the Alzheimer's disease (AD) brain, and the impact on disease progression and neurodegeneration remains an area of active investigation. In this Program Project we propose 5 Projects and 2 supporting Cores. Each Project investigates how inflammation drives brain pathology in AD and how select AD risk factor genes (identified in genome-wide association studies (GWAS)) contribute to the progression of inflammation-driven pathogenesis. The common mechanistic thread linking the Projects is the idea that inflammation and beta-amyloid (A) impair endosomal trafficking and autophagy, which ultimately drives neuronal dysfunction, impaired synaptic plasticity, and deteriorating cognitive health. The team leading the projects has a long history of collaboration and major contributions to the AD field. Project 1: Intracellulr amyloid accumulation, innate immunity and pathogenesis. Charles Glabe, Project Leader. Project 1 proposes that the accumulation of intracellular A contributes to pathogenesis by activating an innate inflammatory cascade that represents a futile attempt to degrade or eliminate A via activation of autophagy. Project 2: Inflammation and A Impair BDNF Signaling and the Regulation of Synaptic Plasticity, Carl Cotman, Project Leader. Project 2 proposes that inflammation and A compromise synaptic plasticity and neuronal viability by impairing, endosomal trafficking and neurotrophic factor signaling, in particular BDNF-TrkB. Project 3: Linking A and tau pathology through IL-1 signaling: relevance of changes in protein trafficking and clearance mechanisms for the disease progression. Frank LaFerIa, Project Leader. Project 3 proposes that a cascade exists by which A species provoke inflammation, which subsequently drives tau pathology. Project 4: Neuroprotection vs. neuroinflammatlon induced by complement proteins and receptors. Andrea Tenner, Project Leader. Project 4 will define the molecular basis of C1q dependent neuroprotection and the functional consequences of CR1 gene polymorphisms, a risk factor for AD. Project 5: PICALM, oligomeric A and inflammation in neurovascular pathogenesis in Alzheimer's disease, David Cribbs, Project Leader. Project 5 investigates how A and inflammation affect cerebrovascular function, and incorporates AD risk factor genes that are linked to inflammation/endosomal processing.